With the wide-spread integration of next-generation sequencing technology over the past several years, comprehensive genomic studies have shown that prostate cancers can be classified into different molecular subtypes. Identification of these subtypes and molecular drivers of pathogenesis represents an opportunity to design rational precision oncology approaches for treatment. To this end, we have recently identified and characterized a novel molecular subtype of prostate cancer typified by biallelic inactivation of CDK12 and shown that it is enriched in cases of metastatic castration-resistant prostate cancer (mCRPC). CDK12-mutant prostate cancers exhibit a distinct genomic instability pattern from other prostate cancer subtypes, including homologous recombination and mismatch repair-deficient, that is associated with a focal tandem duplication (FTD) phenotype. Importantly, CDK12-FTDs lead to an elevated neoantigen burden from increased gene fusions, and this is mirrored by an active immune response and increased T cell trafficking in the tumor microenvironment. Accordingly, preliminary results from mCRPC patients in our cohort suggest that they may have a higher likelihood of response to immune checkpoint blockade. We, therefore, hypothesize that inactivation of CDK12 results in an immunogenic class of mCRPC that may benefit from immune-directed therapies. This hypothesis will be explored through the following Specific Aims: Aim 1: Define the functional relevance of CDK12 loss to prostate cancer biology and identify synthetic lethal targets. Experiments in this Aim will focus on in vitro methods, bioinformatics analyses, and a CRISPR screen to examine how CDK12 loss impacts prostate cancer pathogenesis and drives the emergence of an immunogenomic phenotype. Aim 2: Determine the impact of Cdk12 ablation on prostate tumor growth and immune response in vivo. We will generate several Cdk12-null mouse prostate models to directly evaluate the role of Cdk12 in prostate tumorigenesis and response to immune checkpoint blockade. Aim 3: Identify molecular determinants of response in the first clinical trials of immune checkpoint blockade for CDK12-mutant mCPRC patients. Using samples from our Phase II trial (IMPACT) of nivolumab and ipilimumab in CDK12-mutant patients, we will analyze changes in the immune response and determine tumor-intrinsic biomarkers of response. Together, completion of these Aims will define the role of CDK12 in prostate tumorigenesis and assess precision oncology approaches for this recently identified subtype of prostate cancer.